Peroxisome proliferator activated receptor alpha

Fibrates work by reducing apolipoproteins B, C-III (an inhibitor of LPL), and E, and increasing apolipoproteins A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-a), a nuclear receptor involved in cellular function. The changes in these apolipoproteins result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL. 

PPAR-a peroxisome proliferator-activated receptor-alpha... 

Fruchart JC, Duriez P, Staels B. Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 1999 10 245-257. 

S, Papiha SS, Dai R, et al. The human peroxisome proliferator-activated receptor alpha gene identification and functional characterization of two natural allelic variants. Pharmacogenetics 2000 10 321-333. 

Both MOZ and MORF have also been linked to control of transcription. In initial analyses, these MYST HATs were found to contain potent trans-activation domains in their C-termini (Champagne et al, 1999 2001). Follow-up studies demonstrated that the two proteins can indeed function as transcriptional co-activators for two Runt-domain transcription factors - Runxl and 2 (also referred to as AMLl 3) (Kitabayashi et al., 2001a Pelletier et al., 2002). Furthermore, MORF has been found in the co-activator complex associated with the peroxisome proliferator-activated receptor alpha in rat liver (Surapureddi et al., 2002). 

Dewald O, Sharma S, Adrogue J, et al. Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity. Circulation. Jul 19 2005 112(3) 407 15. 

Young ME, Laws FA, Goodwin GW, et al. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem. Nov 30 2001 276(48) 44390 4395. 

Hsu, M.H., Palmer, C.N., Griffin, K.J. Johnson, E.F. (1995) A single amino acid change in the mouse peroxisome proliferator-activated receptor alpha alters transcriptional responses to peroxisome proliferators. Mol. Pharmacol., 48, 559-567 Huber, W.W., Grasl-Kraupp, B. Schulte-Hermann, R. (1996) Hepatocarcinogenic potential of di-(2-ethylhexyl) phthalate in rodents and its implications on human risk. Grit. Rev. Toxicol., 26, 365-481... 

Tugwood, J.D., Holden, P.R., James, N.H., Prince, R.A. Roberts, R.A. (1998) A peroxisome proliferator-activated receptor-alpha (PPARa) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARa implications for species differences in responses to peroxisome proliferators. Arch. Toxicol., 72, 169-177 Turner, J.H., Petricciani, J.C., Crouch, M.L. Wenger, S. (1974) An evaluation of the effects of diethylhexyl phthalate (DEHP) on mitotically capable cells in blood packs. Transfusion, 14, 560-566... 

Motojima, K., Passilly, R, Peters, J.M., Gonzalez, F.J. Latruffe, N. (1998) Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gatmna activators in a tissue- and inducer-specific manner. J. biol. Chem., 273, 16710-16714... 

Tugwood, JD., Holden, P.R., James, N.H., Prince, R.A. Roberts, R.A. (1998) Isolation and characterization of a functional peroxisome proliferator-activated receptor-alpha from guinea pig. Toxicol., 72, 169-177... 

The effect of dietary fats on hypertriglyceridemia is dependent on the disposition of double bonds in the fatty acids. Omega-3 fatty acids found in fish oils, but not those from plant sources, activate peroxisome proliferator-activated receptor-alpha (PPAR- ) and can induce profound reduction of triglycerides in some patients. They also have antiinflammatory and antiarrhythmic activities. In contrast, the omega-6 fatty acids present in vegetable oils may cause triglycerides to increase. 

PPAR- Peroxisome proliferator-activated receptor-alpha VLDL Very low density lipoproteins... 

Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 2000 275 28918-28928. 

Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999 103 1489-1498. 

Kroetz DL, Yook P, Costet P, Bianchi P, Pineau T. Peroxisome proliferator-activated receptor alpha controls the hepatic CYP4A induction adaptive response to starvation and diabetes. J Biol Chem 1998 273 31581-31589. 

Lemberger T, Saladin R, Vazquez M, et al. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem 1996 271 1764-1769. 

Cheung C, Akiyama TE, Ward JM, Nicol CJ, Feigenbaum L, Vinson C, Gonzalez FJ. Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res 2004 64 3849-3854. 

LoVerme, J., Russo, R., La Rana, G., Fu, J., Farthing, J., Mattace-Raso, G., Meli, R., Hohmann, A., Calignano, A., and Piomelli, D. (2006). Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J. Pharmacol. Exp. Ther. 319, 1051—1061. 

Benani, A., Heurtaux, T., Netter, P., and Minn, A. (2004). Activation of peroxisome proliferator-activated receptor alpha in rat spinal cord after peripheral noxious stimulation. Neurosci. Lett. 369,... 

Cristiano, F., Bernardo, A., and Ceru, M. P. (2001). Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J. Neurocytol. 30, 671—683. Cullingford, T. E., Bhakoo, K., Peuchen, S., Dolphin, C. T., Patel, R., and Clark, J. B. (1998). Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor alpha, beta, and gamma in rat central nervous system. J. Neurochem. 70, 1366-1375. 

Cuzzocrea, S., Di Paloa, R., Mazzon, E., Genovese, T., Muia, C., Centorrino, T., and Caputi, A. P. (2004). Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice. Lab. Invest. 84, 1643-1654. 

Forman, B. M., Chen, J., and Evans, R. M. (1997). Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA 94, 4312-4317. 

Gervois, P., Torra, I. P., Chinetti, G., Grotzinger, T., Dubois, G., Fruchart, J. C., Fruchart-Najib, J., Leitersdorf, E., and Staels, B. (1999). A truncated human peroxisome proliferator-activated receptor alpha splice variant with dominant negative activity. Mol. Endocrinol. 13, 1535—1549. 

Jhaveri, M. D., Richardson, D., Robinson, I., Garle, M. J., Patel, A., Sun, Y., Sagar, D. R., Bennett, A. J., Alexander, S. P., Kendall, D. A., Barrett, D. A., and Chapman, V. (2008). Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabi-noid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 55, 85—93. 

Woerly, G., Honda, K., Loyens, M., Papin, J. P., Auwerx, J., Staels, B., Capron, M., and Dombrowicz, D. (2003). Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation.. Exp. Med. 198, 411—421 -... 

Hasmall SC, James NH, Macdonald N, et al. 2000. Species differences in response to diethylhexylphthalate suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression. Arch Toxicol 74 85-91. 

Palmer CNA, Griffin KJ, Raucy JL, et al. 1998. Peroxisome proliferator activated receptor-alpha expression in human liver. MolPharmacol53 14-22. 

Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M., and Lehmann,J. M. (1997). Fatty Acids and Eicosanoids Regulate Gene Expression Through Direct Interactions with Peroxisome Proliferator-Activated Receptors Alpha and Gamma. Proc. Natl. Acad. Sci. U.S.A. 94, 4318-4323. 

Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., and Kadowaki, T. (1998). A novel insulin sensitizer acts as a coligand for peroxisome proliferator-Activated Receptor-Alpha (PPAR-alpha) and PPAR-Gamma Effect of PPAR-Alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats. Diabetes AT, 1841-1847. 

Moffit JS, Aleksunes LM, Maher JM, et al. Induction of hepatic transporters multidrug resistance-associated proteins (Mrp) 3 and 4 by clofibrate is regulated by peroxisome proliferator-activated receptor alpha. J Pharmacol Exp Ther 2006 317 537-545. 

Sheu, M.Y., Fowler, A.J., Kao, J. et al. Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models. J. Invest. Dermatol. 2002, 118 94-101. 

Hnang B, Wn P, Bowker-Kinley MM, and Harris RA (2002) Regnlation of pyruvate dehydrogenase kinase expression hy peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51,276-83. 

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